Sustained-release drug dosage units of terazosin

ABSTRACT

A sustained-release coating composition is described that contains an ethylcellulose and/or a methacrylic methylester together with a plasticizer and a detackifying agent. Sized drug granules are coated with this composition and then mixed with a polymeric composition containing at least one viscosity agent and formed into drug dosage units for the administration and sustained release of the drug in a patient. 
     The sustained-release drug dosage units described produce a continuous, slow release of the drug at a therapeutically effective dosage level when administered to a patient.

This is a division of U.S. patent application Ser. No. 709,952, filedJun. 4, 1991, now U.S. Pat. No. 5,169,642, a continuation-in-part ofU.S. patent application Ser. No. 605,152, filed Nov. 2, 1990,(abandoned) which is a continuation-in-part of U.S patent applicationSer. No. 444,458, filed Dec. 1, 1989,(abandoned) which is acontinuation-in-part of U.S. patent application Ser. No. 353,809, filedMay 22, 1989 (abandoned), which is a continuation-in-part of U.S. patentapplication Ser. No. 211,495, filed Jun. 24, 1988 (abandoned).

TECHNICAL FIELD

The present invention relates to sustained-release drug dosage units.Compositions and methods for preparing sustained-release dosage unitsare described.

BACKGROUND OF THE INVENTION

The use of sustained-release drug dosage units for the oraladministration of drugs to a patient has several therapeutic advantages.A therapeutically effective systemic level of a drug can be maintainedover an extended time period without the necessity of multiple dailydrug administration. Some drugs are toxic or otherwise deleterious inhigh concentrations, and thus require multiple administration oflow-level amounts of these drugs to patients. Such administrationresults in a bolus rise in drug concentration initially, above the mosteffective therapeutic level, and a concomitant decrease over time belowthis level, producing a high-low fluctuation in blood levels of thedrug. Sustained-release dosage forms overcome this problem by releasingthe drug in small amounts throughout a predetermined time period andthus maintaining the drug level in the blood within a narrowtherapeutically effective range as the rate of drug release and systemicdrug removal are maintained in balance.

Numerous methods and compositions for preparing controlled-release drugcompositions are known, and include those described in U.S. Pat. No.4,572,833 to Pedersen, et al.; U.S. Pat. Nos. 4,713,248 and 4,716,041 toKjornaes, et al; U.S. Pat. No. 4,772,475 to Fukui, et al.; U.S. Pat. No.4,756,911 to Drost, et al.; U.S. Pat. No. 4,786,506 to Fontanelli; U.S.Pat. No. 4,351,825 to Southman, et al; U.S. Pat. No.4,252,786 to Weiss,et al.; U.S. Pat. No. 4,199,560 to Gyarmati, et al; and Colombo, et al.,European Patent Application No. EP0092060.

SUMMARY OF THE INVENTION

The present invention is directed to a sustained-release drug coatingcomposition, sustained-release coated drug granules, sustained-releasedrug dosage units and methods for the preparation and administration ofa sustained-release drug dosage unit.

More particularly, the present invention is directed to drug granulescoated with a composition which slows drug release. These coated druggranules are mixed with polymeric materials to form a dosage unit thatfurther slows release of the drug. The resulting composition provides acontinuous slow release of a therapeutically effective level of drug inthe patient.

The sustained-release drug coating composition of the present inventioncomprises about 2 to about 20 weight percent (w/v) of an ethylcelluloseand/or a methacrylic methylester, about 0.1 to about 5.0 weight percent(w/v) of a plasticizer and about 0.5 to about 20 weight percent (w/v) ofa detackifying agent.

A drug dosage unit of the present invention contains sustained-releasecoated drug granules together with at least one viscosity agent such asmethylcellulose, hydroxypropylmethylcellulose, povidone,hydroxypropylcellulose, and the like. The dosage unit is preferably atablet formed by compression of this mixture.

A method of treatment of the present invention comprises orallyadministering a drug dosage unit of the present invention to a patientin need of such treatment.

The present invention is also directed to a method for the preparationof a sustained-release drug dosage unit. In this method, a drug is firstadmixed with a detackifying agent such as silica gel and wetted with asolvent such as ethanol with further mixing to form drug granules. Thedrug granules are then dried and sized, such as by sifting throughscreens, to obtain granules of a desired size; larger granules are thenmilled and sized to produce more drug granules of the desired size. Theappropriately sized granules are then admixed with a sustained-releasedrug coating composition of the present invention to produce coated druggranules. The coated drug granules are then mixed with at least oneviscosity agent of the present invention and formed intosustained-release drug dosage units such as tablets.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention is directed to the sustained release of a drugover a predetermined time period following administration to a patient.A drug is formulated into granules and then coated with a coatingcomposition that contains an ethylcellulose and/or a methacrylicmethylester together with plasticizer and a detackifying agent dissolvedor dispersed in a solvent such as ethanol and/or acetone.

As used herein, the term "coating composition" refers to a mixture ofdesignated compounds that when applied to granules of a drug produces aninsoluble coating through which the drug is slowly released.

As used herein, the terms "an ethylcellulose" and "a methacrylicmethylester" refer to both substituted and unsubstituted forms ofethylcellulose and methacrylic methylester, respectively, and includeethylcellulose, hydroxypropylethylcellulose, methacrylic methylester,polymethylmethacrylate, and the like.

As used herein, the term "plasticizer" refers to a component of thecoating composition that has a low vapor pressure and whose presence inthe composition modifies the flexibility and diffusion properties of thecoating composition.

As used herein, the term "detackifying agent" refers to a compound whosepresence in the coating composition reduces the stickiness or adhesionof the coated drug granules.

Plasticizers useful in the coating composition can include castor oil,propylene glycol, polyethylene glycol, acetyl triethyl citrate, acetyltributyl citrate, triethyl citrate, tributyl citrate, and the like.Plasticizers are present in the coating composition of the presentinvention at a concentration of about 0.1 to about 5.0 weight percent(w/v) of the total weight of the composition.

Detackifying agents useful in the present invention include magnesiumstearate, talc, titanium dioxide, silica gel, and the like. Thedetackifying agent is present in the coating composition of the presentinvention at a concentration of about 0.5 to about 20 weight percent(w/v) of the total weight of the composition.

Drugs useful in the present invention are orally administerable drugsand preferably include divalproex sodium and valproic acid, its salts orderivatives thereof. Other drugs useful in the present invention includeterazosin(2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine),its salts, hydrates or derivatives thereof. Terazosin, its salts,hydrates or derivatives thereof can be in the form of a racemic mixtureor the individual R(+)- or S(-)- enantiomer.

Derivatives of valproic acid include amides and esters thereof. Estersof valproic acid include the 2-propylpentanol-di-n-propylacetate andglycerol tri(dipropylacetate).

Salts of valproic acid refer to salts with alkali metals or alkalineearth metals, such as sodium, potassium, calcium or magnesium or withorganic bases and the like.

Salts of terazosin refer to the relatively non-toxic, inorganic andorganic acid addition salts of the compound of terazosin. These saltscan be prepared in situ during the final isolation and purification ofthe compound or by separately reacting the purified compound in its freebase form with a suitable organic or inorganic acid and isolating thesalt thus formed. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate,valerate, oleate, palmitate, stearate, laurate, borate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, naphthylate, mesylate, tosylate, glucoheptonate, lactobionate,laurylsulphonate salts and the like. (See, for example S. M. Berge, etal., "Pharmaceutical Salts," J. Pharm. Sci., 66: 1-19 (1977) which isincorporated herein by reference.) The particularly preferred salt ofhytrin is the hydrochloride.

In a preferred embodiment, granules of divalproex sodium or terazosinhydrochloride dihydrate are coated with a composition containingethylcellulose, castor oil and magnesium stearate in a solvent mixturesuch as ethanol and acetone.

In a particularly preferred embodiment, a sustained-release drugparticle composition of the present invention comprises about 62 weightpercent divalproex sodium, about 2.6 weight percent silica gel, about11.6 weight percent ethylcellulose, about 1.9 weight percent castor oil,about 11.6 weight percent magnesium stearate, from about 0.04 to about0.09 weight percent of an edible dye, about 1.0 weight percent povidoneand about 9.7 weight percent microcrystalline cellulose.

In another particularly preferred embodiment, a sustained-release drugparticle composition of the present invention comprises about 12.9weight percent terazosin monohydrochloride dihydrate, about 5.5 weightpercent povidone, about 53.6 weight percent sugar spheres, about 8.0weight percent ethylcellulose, about 1.3 weight percent castor oil,about 8.0 weight percent magnesium stearate and about 10.7 weightpercent microcrystalline cellulose.

The sustained-release coated drug granules of the present invention areformed into drug dosage units, such as tablets, by admixing themtogether with at least one viscosity agent, and preferably with twoviscosity agents, prior to forming the composition into tablets.Illustrative viscosity agents include methylcellulose,hydroxypropylmethylcellulose, povidone and hydroxypropylcellulose.

As used herein, the term "drug dosage unit" refers to a dosage form thatis capable of being orally administered to produce a sustained releaseof a drug therefrom. Illustrative drug dosage units include tablets,capsules and lozenges.

As used herein, the term "viscosity agent" refers to an ingredient of adrug dosage unit which forms an insoluble or non-disintegratingpolymeric matrix in which the coated drug granules of the presentinvention are enclosed, and from which the drug is slowly released.

A preferred drug dosage unit of the present invention contains about 2.0to about 80 weight percent of sustained-release coated drug granules,about 0 to about 35 weight percent of calcium phosphate, about 2 toabout 30 weight percent of a first viscosity agent and about 0 to about30 weight percent of a second viscosity agent.

In a particularly preferred embodiment, the drug granules containdivalproex sodium, and the dosage unit contains from about 63 to about65 weight percent of sustained-release coated granules of divalproexsodium, from about 3.5 to about 4.5 weight percent of methylcellulose,from about 14.2 to about 14.6 weight percent ofhydroxypropylmethylcellulose, from about 14.2 to abut 14.6 weightpercent of dibasic calcium phosphate, from about 0.7 to about 0.8 weightpercent of stearic acid and from about 1.5 to about 2.2 weight percentof talc.

In another particularly preferred embodiment, the drug granules containterazosin monohydrochloride dihydrate, and the dosage unit contains fromabout 2.6 to about 26.4 weight percent of sustained-release coatedgranules of terazosin hydrochloride dihydrate, about 2.5 weight percentof methylcellulose, about 10.5 weight percent ofhydroxypropylmethylcellulose, about 34.0 weight percent of dibasiccalcium phosphate, about 1.1 weight percent of stearic acid and about1.9 weight percent of talc.

The present invention is also directed to a method of treatment in whicha sustained-release drug dosage unit is administered to a patient inneed of such treatment for the sustained release of a drug such asdivalproex sodium or terazosin. In this method, a drug dosage unit ofthe present invention is orally administered to a patient, to releasethe drug systemically over a period of about 10 to about 12 hours.

A drug dosage unit of the present invention is prepared by admixing adrug, such as divalproex sodium or valproic acid, it salts orderivatives thereof, or terazosin, its salts, hydrates or derivativesthereof, with a detackifying agent such as silica gel in a solvent, suchas ethanol, to produce drug granules. The drug granules are then dried,such as by warm air, and sized, such as by sifting through screens, toobtain granules of a desired size. Large granules are further milled andsized to obtain granules of the desired size. These granules are thenmixed with a coating composition of the present invention to producecoated granules, which are then mixed with a composition containing atleast one viscosity agent, and then formed into an appropriate drugdosage unit, such as tablets.

As used herein, the term "sizing screen" refers to a screen havingopenings of a definite specified size over which a mixture of solidparticles, such as drug granules, is placed to fractionate the particlesby size. Particles smaller than the openings fall through the screen andare collected. Particles larger than the specified size of the openingsare retained and separated from the smaller particles. In the presentinvention, such retained particles are further milled to produce smallerparticles and then placed over the screen to collect additionalparticles that can pass through the screen openings.

In a preferred embodiment of this method, granules of divalproex sodiumare mixed with silica gel and suspended in ethanol. The granules arethen dried in warm air and passed through sizing screens to producegranules smaller than a selected size. The sized granules are then mixedwith a coating composition comprising ethycellulose, castor oil,magnesium stearate, acetone and ethanol. The coated drug granules arethen sifted through another screen to obtain desired-size coatedgranules which are then blended together with methylcellulose,hydroxypropylmethylcellulose, calcium phosphate, stearic acid and talcand compressed into tablets.

In another preferred embodiment of this method, terazosin hydrochloridedihydrate and povidone in ethanol are coated on sugar spheres. Theterazsosin particles are then mixed with a coating compositioncomprising ethylcellulose, castor oil, magnesium stearate, ethanol andacetone. The coated drug particles are sifted through a sizing screenand blended together with methylcellulose,hydroxylpropylmethylcellulose, calcium phosphate, stearic acid and talcand compressed into tablets

The following examples will serve to further illustrate the invention.

EXAMPLE 1 Divalproex Sodium Tablets 1A Preparation of Granular DrugParticles

Divalproex sodium (19.2 kg) was mixed with pharmaceutical-grade silicagel (800 g, Syloid 244) and the mixture was milled in a Fitzmill atmedium speed with knives forward through a 2A band, for 5 minutes.

The milled mixture was then placed in a granulation mixer, and ethanol(1.2 kg, 200 proof) was added during mixing at low speed until themixture was granular (about 3 minutes). The granular mixture was removedand dried in an Aeromatic Fluid Bed Dryer at 45° C. to 50° C. Thegranulated mixture was then sifted through a 12-mesh and then a 24-meshscreen. The material that passed through the 12-mesh screen and that wasretained on the 24-mesh screen was collected. The material retained onthe 12-mesh screen was re-milled in a Fitzmill at medium speed through a2A band and then resifted through 12-mesh and 24-mesh screens.

1B Drug Granule Coating Composition

Ethanol (12 liters, 200 proof) and acetone (40 liters) were mixedtogether. Triethyl citrate (600 g) and ethylcellulose (3600 g) wereslowly added to the mixture, and mixing continued to produce a clearsolution. Magnesium stearate (3600 g) and blue dye (12 g, FD and C No.2) were added with mixing. Acetone was then added to bring the volume to60 liters.

1C Compression Enhancing Coating Composition

Ethanol (25 liters, 200 proof) was combined with povidone (300 g) andmixed for about one hour to produce a clear solution. Microcrystallinecellulose (3000 g) was added to the solution with continued mixing.Ethanol (200 proof) was then added to bring the volume to 30 liters.

1C Coating of Drug Granules

The coating composition of EXAMPLE IB was applied to the drug granules(12-24 mesh) of EXAMPLE 1A at a concentration of 3 liters of coatingcomposition per 1 kg of drug granules. The compression coatingcomposition of EXAMPLE 1C (1.5 liters per kg of particles) was added tothe mixture. The particles were dried by fluidizing without spraying for30 minutes to produce a loss on drying (L.O.D.) of not more than 0.5percent at 110° C.

The coated particles were collected and sifted through a 10-mesh screenand the coated particles that passed through the screen were collected.

1E Preparation of Tablets

The coated particles (4.2 kg) obtained in EXAMPLE ID were combined withmethylcellulose (250 g, 15 cps), hydroxypropylmethylcellulose (950 g,USP 2910, 100 cps), calcium phosphate (950 g), stearic acid (50 g) andtalc (100 g), and mixed in a blender. The blended mixture was thencompressed into tablets.

EXAMPLE 2 Divalproex Sodium Tablets 2A Preparation of Granular DrugParticles

Divalproex sodium (1440 kg) was mixed with pharmaceutical-grade silicagel (60 kg, Syloid 244) and the mixture was milled in a Fitzmill atmedium speed with knives forward through a 2A band, for 5 minutes.

The milled mixture was then placed in a granulation mixer with ethanol(100 liters, 200 proof) and mixed at low speed until the mixture wasgranular. The granular mixture was removed and dried in an AeromaticFluid Bed Dryer at 45° C. to 50° C. to produce a loss on drying (L.0.D.)of not more than 0.5 percent. The granulated mixture was then siftedthrough a 12-mesh and then a 24-mesh screen. The material that passedthrough the 12-mesh screen and that was retained on the 24-mesh screenwas collected. The material retained on the 12-mesh screen was re-milledin a Fitzmill at medium speed through a 2A band and then resiftedthrough 12-mesh and 24-mesh screens.

2B Drug Granule Coating Composition

Ethanol (150 liters, 200 proof) and acetone (450 liters) were mixedtogether. Castor oil (7.5 kg) and ethylcellulose (45 kg) were slowlyadded to the mixture, and mixing continued to produce a clear solution.Magnesium stearate (45 kg) and blue dye (300 g, FD and C No. 2) andyellow dye (56.25 g, D and C No. 10) were added with mixing. Acetone wasthen added to bring the volume to 750 liters.

2C Compression Enhancing Coating Composition

Ethanol (280 liters, 200 proof) was combined with povidone (7.6 kg) andmixed for about one hour to produce a clear solution. Microcrystallinecellulose (76 kg) was added to the solution with continued mixing.Ethanol (200 proof) was then added to bring the volume to 380 liters.

2D Coating of Drug Granules

The coating composition of EXAMPLE 2B was applied to the drug granules(12-24 mesh) of EXAMPLE 2A at a concentration of 3 liters of coatingcomposition per 1 kg of drug granules. (Inlet Air Temp.: 50° C.;Relative Humidity: 0%; Chamber Pressure: -10 mm H₂ O; Atomization AirPressure; 65 PSIG; Process Air Flow Rate: 4000 SCMH; Solution Flow Rate:310 ml/minute/nozzle). The compression coating composition of EXAMPLE 2C(0.75 liters per kg of particles) was added to the mixture. (Inlet AirTemp.: 48°-50° C.; Relative Humidity: 0%; Chamber Pressure: -10 mm H₂ O;Atomization Air Pressure: 40 PSIG; Process Air Flow Rate: 6000 SCMH;Solution Flow Rate: 350 ml/minute/nozzle). The particles were dried byfluidizing without spraying for 20 minutes to produce a loss on drying(L.O.D.) of not more than 0.5 percent at 110° C.

The coated particles were collected and sifted through a 10-mesh screenand the coated particles that passed through the screen were collected.

2E Preparation of Tablets

The coated particles (98.04 kg) obtained in EXAMPLE 2D were combinedwith methylcellulose (6.75 kg, 15 cps), hydroxypropylmethylcellulose(22.5 kg, USP 2208, 100 cps), calcium phosphate (22.5 kg), stearic acid(1.125 kg) and talc (3.375 kg), and mixed in a blender. The blendedmixture was then compressed into tablets.

EXAMPLE 3 Bioavailability Study

Drug tablets were administered to 15 adult males under fasting andnon-fasting conditions.

Two formulations of divalproex sodium were utilized to determinebioavailability data.

Formulation A was the controlled-release dosage form of the presentinvention containing 500 mg valproic acid equivalent per tablet andprepared according to the general procedure of Example 2.

Formulation B was an enteric coated tablet (Depakote®) containing 250 mgvalproic acid equivalent per tablet.

A single dose of 1000 mg valproic acid equivalent (two tablets ofFormulation A, or four tablets of Formulation B) was administered toeach subject. Each subject was a healthy adult male between 18 and 40years of age. Formulation A was administered under fasting andnon-fasting conditions.

The subjects were housed and supervised for four and one-half days ineach study period, from a minimum of 12 hours prior to administration ofthe drug dose through the 72-hour blood collection.

The subjects abstained from all food and beverage except for scheduledmeals and water during the study period. Under non-fasting conditions,the subjects were served a meal one-half hour prior to administering adose of Formulation A. Under fasting conditions, the subjects wereserved a meal 2 hours after administration of doses of Formulations Aand B, respectively. All subjects received a meal 6 hours after drugadministration and, thereafter, at 11 hours, 24.5 hours, 28 hours, and34 hours after drug administration. Seven-milliliter blood samples werecollected in heparinized tubes from each subject prior to drugadministration (0 hour) and at 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 24, 30,36, 48, 60 and 72 hours after drug administration, and stored at 0° C.until separation into plasma (within 3 hours after collection and plasmawas stored at -10° C.).

The results obtained are shown in TABLE I.

                  TABLE I                                                         ______________________________________                                        Plasma Valproic Acid Concentration (μg/ml)                                 Time   Formulation A                                                                              Formulation A                                                                             Formulation B                                 (hours)                                                                              (fasting)    (non-fasting)                                                                             (fasting)                                     ______________________________________                                         0     0.0     (0.1)      0.0   (0.0) 0.0   (0.1)                              1     3.9     (1.2)      1.4   (0.9) 1.4   (2.6)                              2     12.3    (3.1)      12.8  (21.9)                                                                              47.2  (36.9)                             3     21.3    (4.7)      20.6  (23.8)                                                                              72.0  (31.2)                             4     36.1    (23.1)     28.4  (19.0)                                                                              60.5  (30.5)                             6     35.2    (6.7)      43.1  (11.2)                                                                              59.4  (19.5)                             8     47.1    (8.2)      49.4  (7.7) 58.7  (7.4)                             10     54.3    (7.4)      55.7  (9.9) 52.2  (6.7)                             12     60.1    (9.0)      58.0  (7.7) 50.1  (13.0)                            15     52.0    (7.9)      51.0  (7.0) 41.5  (10.6)                            18     44.8    (6.9)      42.9  (7.8) 34.3  (9.6)                             24     34.3    (6.3)      33.9  (5.8) 27.1  (8.9)                             30     23.4    (6.4)      22.6  (4.7) 18.3  (5.7)                             36     17.5    (4.4)      16.7  (4.3) 13.6  (4.6)                             48     10.0    (3.5)      9.7   (3.4) 8.4   (3.4)                             60     5.6     (2.3)      5.5   (2.2) 4.8   (2.4)                             72     3.7     (1.8)      3.5   (1.8) 3.1   (1.9)                             T.sub.max                                                                            10.9    (3.4)      11.0  (2.7) 4.3   (3.3)                             C.sub.max                                                                            65.1    (11.9)     63.7  (12.6)                                                                              87.0  (9.5)                             AUC    1585.0  (278.8)    1557.6                                                                              (244.0)                                                                             1527.9                                                                              (264.6)                           ______________________________________                                         T.sub.max = Time of peak concentration (hours).                               C.sub.max = Peak concentration (μg/ml).                                    AUC = Area under Plasma Concentration  Time Curve, 0 to 72 hours (μg       × hr/ml).                                                          

The values in parentheses represent the standard deviation.

The results show that the controlled-release dosage form of the presentinvention had a lower C_(max) in plasma in both fasting and non-fastingsubjects than the enteric coated tablets, and maintained a higher plasmaconcentration of valproic acid over time.

EXAMPLE 4 Terazosin Hydrochloride Dihydrate Tablets 4A Preparation ofDrug Particles

Terazosin hydrochloride dihydrate (48.0 kg) was mixed with povidone(16.0 kg) and ethanol (300 liters, 200 proof). After mixing, ethanol(200 proof) was added to bring the final volume to 400 liters.

200 kg of sugar spheres (40-50 mesh) were coated with theabove-mentioned solution of terazosin. (Inlet Air Temp.: 52° C.;Relative Humidity: 15%; Chamber Pressure: -10 mm H₂ O; Atomization AirPressure; 65 PSIG; Process Air Flow Rate: 3000-3500 SCMH; Solution FlowRate: 200-215 ml/minute/nozzle).

4B Drug Particle Coating Composition

Ethanol (100 liters, 200 proof) and acetone (300 liters) were mixedtogether. Ethylcelluose (30 kg) and castor oil (5.0 kg) were slowlyadded to the mixture and mixing continued to obtain a solution.Magnesium stearate (30 kg) was added with mixing and acetone was thenadded to bring the final volume to 500 liters.

4C Compression Enhancing Coating Composition

Ethanol (140 liters, 200 proof) was combined with povidone (4.0 kg) andmixed for about 15 minutes to obtain a clear solution. Microcrystallinecellulose (40.0 kg) was added to the solution with continued mixing.Ethanol (200 proof) was added to bring the final volume to 200 liters.

4D Coating of Drug Particles

The drug particles of Example 4A were coated with the particle coatingcomposition of Example 4B (2.5 liters per kg of nonpareils). (Inlet AirTemp.: 48° C.; Relative Humidity: 15%; Chamber Pressure: -10 mm H₂ O;Atomization Air Pressure; 65 PSIG; Process Air Flow Rate: 3600 SCMH;Solution Flow Rate: 200-220 ml/minute/nozzle). The coated particles weredried by fluidizing without spraying for 20 minutes. The dried coatedparticles were sifted through a 20/60 mesh sifter.

The sifted particles were then coated with the compression enhancingcoating composition of Example 4C (1.0 liters per kg of nonpareils).(Inlet Air Temp.: 50° C.; Relative Humidity: 15%; Chamber Pressure: -10mm H₂ O; Atomization Air Pressure; 40 PSIG; Process Air Flow Rate: 3600SCMH; Solution Flow Rate: 180 ml/minute/nozzle). The coated particleswere dried by fluidizing without spraying for 20 minutes to produce aloss on drying (L.0.D.) of not more than 1.5%. The dried coatedparticles were sifted through a 20/60 mesh sifter. The particles thatpassed through the 20 mesh screen but that did not pass through the 60mesh screen were collected.

4E Placebo Particle Coating Composition

Ethanol (200 liters, 200 proof) and acetone (600 liters) were mixedtogether. Ethylcellulose (60 kg) and castor oil (10 kg) were slowlyadded to the mixture and mixing continued to obtain a solution.Magnesium stearate (60 kg) was added with mixing and acetone was addedto bring the final volume to 1000 liters.

4F Compression Enhancing Coating Composition

Ethanol (300 liters, 200 proof) was combined with povidone (8.0 kg) andmixed for about 15 minutes to obtain a clear solution. Microcrystallinecellulose (80 kg) was added to the solution with continued mixing.Ethanol (200 proof) was added to bring the final volume to 400 liters.

4G Coating of Placebo Particles

300 kg of sugar spheres (40-50 mesh) were coated with the particlecoating composition of Example 4E (500 liters) (Inlet Air Temp.: 48°-50°C.; Relative Humidity: 30%; Chamber Pressure: -10 mm H₂ O; AtomizationAir Pressure; 65 PSIG; Process Air Flow Rate: 3500-4000 SCMH; SolutionFlow Rate: 310 ml/minute/nozzle). The coated particles were dried byfluidizing without spraying for 15 minutes. The dried coated particleswere sifted through a 20/60 mesh sifter.

The sifted particles were then coated with 200 liters of the compressionenhancing coating of Example 4F. (Inlet Air Temp.: 50° C.; RelativeHumidity: 30%; Chamber Pressure: -10 mm H₂ O; Atomization Air Pressure;40 PSIG; Process Air Flow Rate: 4500 SCMH; Solution Flow Rate: 200ml/minute/nozzle). The coated particles were dried by fluidizing withoutspraying for 20 minutes to produce a loss on drying (L.O.D.) of not morethan 1.5%. The dried coated particles were sifted through a 20/60 meshsifter. The particles that passed through the 20 mesh screen but thatdid not pass through the 60 mesh screen were collected.

4H Preparation of Tablets

Methylcellulose (0.875 kg), hydroxypropyl methylcellulose (3.675 kg),calcium phosphate (11.9 kg), stearic acid (0.4 kg) and talc (0.65 kg)were mixed using a Fitzmill at high speed with knives forward through a1-A band.

The mixture was charged into a blender along with the coated terazosinparticles of Example 4D (2.066 kg) and the coated placebo particles ofExample 4G (15.434 kg) and blended for 10 minutes. The blended mixturewas then compressed into tablets.

EXAMPLE 5 Preparation ofR(+)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamineStep 1--Preparation of R(+)-tetrahydrofuroic acid

Using the procedure detailed in Can. J. Chem., 61:1383-1386 (1983),racemic tetrahydro-2-furoic acid was first converted to a mixture of thediastereomeric brucine salts by reaction with (-)-brucine in ethylacetate. The crude brucine salt of R(+)-tetrahydro-2-furoic acid whichfirst precipitated had a melting point of 191°-197° C. and an opticalrotation [α]_(D) ²³ =-7.86° (C=1, methanol). The material wasrecrystallized three times from ethyl acetate to yield material meltingat 200°-203° C. and having an optical rotation [α]_(D) ²³° C. =-4.8°(C=1, methanol) (literature [α]_(D) =-5.8° (C=1, methanol)).

The salt was acidified to recover R(+)-tetrahydro-2 -furoic acid, b.p.57°-58° C. at 0.1 mm Hg, refractive index, η_(D) ²⁵ =1.4953, opticalrotation [α]_(D) ²²° C. =+33.37° (C=1, chloroform) (literature value[α]_(D) =+30.4° (C=1, chloroform).

Step 2--Preparation ofR(+)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine

R(+)-Tetrahydro-2-furoic acid was dissolved in tetrahydrofuran and 2.0 g(0.017 mole) dicyclohexylcarbodiimide was added followed by 3.50 g(0.017 mole) N-hydroxysuccinimide. The mixture was stirred overnight atroom temperature. The precipitated dicyclohexylurea which formed wascollected by filtration and the residue washed with a small amount oftetrahydrofuran. The solid was discarded and the washings added to thefiltrate.

To the filtrate were added a solution of 4.91 g (0.017 mole) of4-amino-6,7-dimethoxy-2-piperazinyl-4-quinazoline in tetrahydrofuran.The resulting mixture was stirred overnight at room temperature. Thesolid which had precipitated was collected by filtration and washedseveral times with tetrahydrofuran. The washings were combined with thefiltrate which was evaporated to dryness. The residual solid was takenup in a 5/1 mixture of methylene chloride/methanol and the resultingmixture distilled to remove the methylene chloride. The removedmethylene chloride was replaced by an equal volume of methanol, at whichpoint the product began to crystallize from solution. The solution wasallowed to cool to room temperature and stand for several hours,yielding R(+)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine, m.p. 272°-274° C., optical rotation[α]_(D) ²²° C. =34.83° (C=1, 3N hydrochloric acid).

EXAMPLE 6 Preparation ofR(+)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine,hydrochloride salt dihydrate

The hydrochloride salt dihydrate was prepared by heating an ethanolsolution ofR(+)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamineto near reflux and adding slightly more than one equivalent ofconcentrated aqueous hydrochloric acid. Solution occurred immediately,and the solution was allowed to cool to room temperature and stand forseveral hours. The precipitate which formed was collected by filtration,washed with ethanol, and dried to yieldR(+)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine,hydrochloride salt dihydrate having a melting point of 260.5°-263.5° C.and an optical rotation [α]_(D) ²⁸.5° C. =23.9° (C=1, water).

EXAMPLE 7 Preparation ofS(-)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamineStep 1--Preparation of S(-)-tetrahydroduroic acid

Using the procedure detailed in Can. J. Chem., 61:1383-1386 (1983),racemic tetrahydro-2-furoic acid was first converted to a mixture of thediastereomeric ephedrine salts by reaction with (+)-ephedrine in ethylacetate. The crude S(-)-ephedrine salt which first precipitated had amelting point of 114°-115° C. The material was recrystallized four timesfrom ethyl acetate to yield material melting at 115°- 117° C. and havingan optical rotation [α]_(D) ²⁶.5° C. =+13.4° (C=1, methanol) (literature[α]_(D) =+13.8°).

The salt was acidified to recover the S(-)-tetrahydro-2-furoic acid,b.p. 60° C. at 0.5 mm Hg, refractive index, η_(D) ²⁵ =1.4582, opticalrotation [α]_(D) ²² =-32.02° (C=1, chloroform) (literature [α]_(D)=-30.1° (C=1, chloroform)).

Step 2--Preparation ofS(-)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine

The procedure employed was the same as that described above in Example 5for the R(+)-enantiomer, yieldingS(-)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine,m.p. 269.5°-271.1° C., optical rotation [α]_(D) ²²° C. =-26.9° (C=1, 3Nhydrochloric acid).

EXAMPLE 8 Preparation ofS(-)-2-[4-[(tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine,hydrochloride salt

The procedure employed was the same as in Example 6 for the preparationof the hydrochloride salt of the R(+)-enantiomer. M.p. 271.5°-273° C.(dec.), optical rotation [α]_(D) ²⁸.5° C. =-23.1° (C=1, water).

The foregoing description and the EXAMPLES are merely illustrative andare not intended to limit the invention to the disclosed embodiments.Variations and changes which are obvious to one skilled in the art areintended to be within the scope and nature of the invention which aredefined in the appended claims.

What is claimed is:
 1. A sustained-release drug dosage form comprising(1) granules of a drug which is terazosin or a salt or hydrate thereofcoated with a sustained-release coating composition comprising fromabout 2 to about 20 weight percent (w/v) of an ethylcellulose or amethacrylic methylester, from about 0.1 to abut 5.0 weight percent (w/v)of a plasticizer and from about 0.5 to about 20 weight percent (w/v) ofa detackifying agent and (2) a slow release matrix comprising at leastone viscosity agent.
 2. The drug dosage form of claim 1 wherein saidplasticizer is selected from the group consisting of castor oil,propylene glycol, polyethylene glycol, acetyl triethyl citrate, acetyltributyl citrate, triethyl citrate and tributyl citrate.
 3. The drugdosage form of claim 1 wherein said detackifying agent is selected fromthe group consisting of magnesium stearate, talc, titanium dioxide andsilica gel.
 4. The drug dosage form of claim 1 wherein the coatingcomposition comprises from about 2 to about 20 weight percent (w/v) ofethylcellulose, from about 0.1 to about 5.0 weight percent (w/v) ofcastor oil and from about 0.5 to about 20 weight percent (w/v) ofmagnesium stearate.
 5. The drug dosage form of claim 1 wherein said drugis terazosin monohydrochloride dihydrate.
 6. The drug dosage form ofclaim 1 wherein said viscosity agent is selected from the groupconsisting of methylcellulose, hydroxypropylmethylcellulose, povidoneand hydroxypropylcellulose.
 7. The dosage form of claim 1comprising:from about 2.0 to about 80 weight percent sustained releasecoated drug granules; from about 0 to about 30 weight percent calciumphosphate; from about 2 to about 30 weight percent of a first viscosityagent and from about 0 to about 30 weight percent of a second viscosityagent wherein said first and second viscosity agents are independentlyselected from the group consisting of methylcellulose,hydroxypropylmethylcellulose, povidone and hydroxypropylcellulose. 8.The dosage form of claim 1 comprising:from about 2.6 to about 26.4weight percent of sustained-release coated terazosin monohydrochloridedihydrate granules; about 2.5 weight percent of methylcellulose; about10.5 weight percent of hydroxypropylmethylcellulose; about 34.0 weightpercent of calcium phosphate; about 1.1 weight percent of stearic acid;and about 1.9 weight percent of talc.
 9. The drug dosage form of claim 1wherein said drug is R-(+)-terazosin monohydrochloride dihydrate.